Method for Production of Particles of Pharmaceutical Substances and the Use Thereof

ABSTRACT

The invention relates to a method for producing particles with a length-width ratio of less than about 1.4 from a pharmaceutical substance, which method includes the following stages, that is: (a) provision of a melt of the pharmaceutical substance; (b) production of droplets of the melt by spraying into a processing chamber; (c) repeated guiding of solid particles past sprayed droplets in the processing chamber with the aid of a process gas jet which is guided in a defined way and whose temperature is fixed, depending on the solidification point of the melt, so that at least some of the droplets come into contact with particles and solidify thereon; (d) removal of particles from the processing chamber as a function of the particle size. The invention further relates to particles of pharmaceutical substances and the use thereof.

FIELD OF THE INVENTION

The invention relates to a method for producing particles from a melt,to the particles themselves, and to the use thereof. The particles areformed from pharmaceutical substances (medicinal substances and/orexcipients).

BACKGROUND OF THE INVENTION

Fine-particle forms of pharmaceutical substances such as fine powdersare frequently associated with technical processing disadvantages. Inorder to avoid such disadvantages, frequently coarser particles(granules) are provided.

Such particles of pharmaceutical substances can be used to producedosage forms by for example compressing them alone or together withfurther components to give tablets. Medicinal substance-containingparticles may additionally be used packed into capsules or in the formof a powder for a suspension or solution.

A number of methods are known for producing particles. Solvents areemployed in some of the methods. This is disadvantageous because thesolvents must be removed again during the method. Even small amounts ofremaining solvents may impair the product quality. Organic solvents areadditionally undesired from the viewpoint of safety at work andenvironmental protection.

Solidified melt granules (melt granules) are known as alternative. Theyare produced by melting and shock solidification, by casting andcomminuting or by spray congealing in spray towers. These known methodsare, however, associated with disadvantages.

Methods in which a solidified melt is comminuted are rather elaboratebecause they require stages of melting, solidifying and comminutingseparately, for each of which different types of apparatuses arerequired. In addition, it is rather difficult to obtain particulatematerial with a particle size distribution. Moreover, the particlesobtained by comminution have irregular shapes, thus making furtherhandling difficult.

The production of melt granules by solidifying a melt in a spray toweris also associated with disadvantages. There is typically formation of arelatively large proportion of material of unwanted particle size, whichmust be separated off and remelted. The resulting particles areordinarily not uniformly globular, thus impairing their handlingproperties.

A method of the last-mentioned type is described in EP 0 362 731. Themethod is carried out by atomizing an active pharmaceutical ingredientmelt in a spray chilling tower in order to produce active pharmaceuticalingredient particles. Ibuprofen is employed for example as activeingredient. The particles are obtained by cooling droplets of a meltwhich is atomized in a spray chilling tower in the presence ofcrystallization nuclei and is brought into contact with a chilling gas.Desired particles are removed with the aid of a sieve from the powderwhich is formed.

A number of other patents and patent applications also relate to theproduction of medicinal substance particles, specifically of ibuprofenparticles, and to the use thereof for producing certain dosage forms.

EP 0 362 728 A2 relates to a method for obtaining ibuprofen for directtableting. In this case, an ibuprofen melt is solidified on acontact-chilling apparatus and then comminuted. Since the production ofthe particles takes place in two stages, the method is rather elaborate.In addition, the particles have irregular shapes owing to thecomminution process.

U.S. Pat. No. 6,322,816 relates to analgesic products with rapid releaseof active ingredient. A suitable active ingredient is in particularibuprofen. The active ingredient is present in a special adjuvantmatrix.

US 2003/0203026 relates to therapeutic agents, in particular acompressed tablet. This contains a granular component which comprises aplurality of solidified melt granules of a non-steroidalanti-inflammatory drug which has a melting point in the range from 30 to200° C., and a disintegrant uniformly distributed therein. Ibuprofen isa preferred active ingredient. The melt can be solidified by chillingand then comminuted. Alternatively, the melt can be sprayed through anozzle in order to make it possible to solidify the material, which isthen collected.

US 2005/0003000 relates to a method for forming ibuprofen solids, whereadditives are added to a solution of ibuprofen and are removed againlater.

WO 02/07706 relates to a method for coating solid particles, for exampleibuprofen particles. This document is not concerned with the productionof these particles employed as starting material.

WO 94/10993 relates to pharmaceutical formulations of ibuprofen. Theproduction of a particulate dosage form is described inter alia, therebeing provision for addition of an aqueous solution of a binding toibuprofen.

U.S. Pat. No. 5,320,855 relates to chewable tablets which are producedfrom granules of a medicament. The granules in turn are produced byrotogranulation of a mixture of a medicinal substance such as ibuprofenand excipients and is provided with particular coatings.

EP 0 290 168 relates to an ibuprofen tablet with sustained release.There is provided in particular an ibuprofen-containing matrix which isobtained by granulating ibuprofen mixed with excipients in powder formusing a particular solution as granulation liquid.

EP 0 241 126 relates to a solid pharmaceutical composition whichincludes granules which consist essentially of an aggregate of ibuprofencrystals. The method generally includes the compaction of crystallineibuprofen in order to bring about aggregation of the crystallineibuprofen to form an aggregate material, the comminution of theaggregate material and the selection of granules with the desired size.It is possible for example to produce crystalline ibuprofen by wettingwith a solvent. An extrusion then takes place. The granules obtained inthis case are dried.

EP 0 230 322 relates to a pharmaceutical composition with sustainedrelease of the active ingredient. Sugar esthers of higher fatty acidsare employed in this case. The production method includes mixing andgranulating components.

EP 0 250 648 relates to a pharmaceutical product for sustained releaseof ibuprofen. The product is in the form of tablets which comprise theactive ingredient in microspheres. Production takes place by mixing theibuprofen and a binding to give a homogeneous mixture and moisteningwith water. The mixture is then shaped to microspheres by extrusion, andtablets are finally produced therefrom.

WO 96/31197 relates to homogeneous mixtures of low-melting medicinalsubstances and additives for controlled release. One method forproducing such a formulation includes the melting of a medicinalsubstance and an additive at a temperature below 150° C., mixing themedicinal substance and the additive to form a homogeneous mixture, andfinally hardening the homogeneous mixture to form a medicinalsubstance-additive composite material. It is intended to introduce themolten mass into capsules, where it then hardens on cooling.

The prior art further includes proposals for producing granules by usingspouted bed apparatuses. Thus, DE 103 22 062 A1 discloses the productionof granules from various materials by applying liquids in a solid streamin a spouted bed apparatus. Said application is, however, not concernedeither with the specifics of pharmaceutical substances or with theconditions which must be observed when producing particles from a melt.

DE 100 04 939 C1 relates to a controllable gas stream unit for spoutedbed apparatuses. The patent is not concerned with the production of meltgranules.

WO 2004/108911 A2 relates to methods for producing enzyme granules andto such granules. A spouted bed apparatus is employed for theproduction. The application is not concerned with melt granules.

OBJECTS AND BRIEF DESCRIPTION OF THE INVENTION

One object of the present invention is to indicate a method with whichpreferably globular particles of pharmaceutical substances (medicinalsubstances and/or excipients) can be produced from a melt. It isintended in this connection to be able to avoid the disadvantages ofconventional methods. A further object is to produce preferably globularparticles and collections of such particles and to make it possible forthem to be used for producing pharmaceutical dosage forms.

It has been found according to the invention that it is possible tobuild up essentially globular particles from single droplets of a meltwhen the droplets are guided with the aid of a process gas at a suitabletemperature so that particles of melt which has already solidified cancome into contact with droplets anew. A difference from the productionof particles from a melt in a conventional spray tower is that theparticles which form are circulated in a suitable processing chamberuntil they have reached the desired size through repeated addition ofdroplets of the melt.

Accordingly, the invention provides a method for producing particleswith a length-width ratio of less than about 1.4 from a pharmaceuticalsubstance, which method includes the following stages:

-   -   (a) provision of a melt of the pharmaceutical substance;    -   (b) production of droplets of the melt by spraying into a        processing chamber;    -   (c) repeated guiding of solid particles past sprayed droplets in        the processing chamber with the aid of a process gas jet which        is guided in a defined way and whose temperature is fixed,        depending on the solidification point of the melt, so that at        least some of the droplets come into contact with particles and        solidify thereon;    -   (d) removal of particles from the processing chamber as a        function of the particle size.

The invention also provides particles of a pharmaceutical substancewhere the particles have an average particle size of from 0.1 to 3 mmand a length-width ratio of less than about 1.4, and are produced from amelt of the pharmaceutical substance.

BRIEF DESCRIPTION OF THE FIGURE

The invention is explained in more detail below with reference to aFIGURE. This FIGURE depicts diagrammatically a system for carrying outthe method of the invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Some technical terms used in the description and in the claims areexplained below.

A melt is produced by melting a substance with heating to a temperaturewhich is typically in the range from 30° C. to 300° C. The melt ispreferably obtained by complete melting of a substance or mixture ofsubstances, so that a homogeneous phase is formed. Alternatively, solidsubstances can be dispersed in the melt. Unless indicated otherwise, theterm melt is understood here in this wider sense.

The expression “pharmaceutical substance” is intended to refer tomedicinal substances, pharmaceutical excipients and mixtures of suchcomponents. In a preferred embodiment, the pharmaceutical substance is amedicinal substance.

Since it is intended according to the invention to produce particlesfrom pharmaceutical substances by melt granulation, it is furthernecessary for the substances to be meltable without substantialdecomposition, that is to say without impairing their pharmaceuticaluse. Substances which undergo decomposition on melting cannot beprocessed according to the invention unless the melting point can bereduced by suitable additions to make the melting and processingpossible. A person skilled in the art is able to establish by testswhether the quality is still sufficient after the melting andsolidification. Tests for ensuring the quality of numerouspharmaceutical substances are laid down in the appropriatepharmacopoeias.

Examples of medicinal substances which can be processed by meltgranulation are divalproex sodium, ibuprofen, ramipril, dibenzyline,erythrityl tetranitrate, isosorbide dinitrate, methosuximide,ketoprofen, gemfibrozil, paroxetine hydrochloride and trimipraminemaleate. A medicinal substance which is preferred according to theinvention is ibuprofen.

Examples of pharmaceutical excipients are low-melting binders, forexample gelatine and starch compositions, and low-melting insolublepolymers.

A particle is referred to as globular according to the invention if thelength-width ratio (meaning the ratio of the length (largest dimension)of the particle divided by the width (smallest dimension) which is fixedat an angle of 90° in relation to the length) is less than about 1.4.The length-width ratio of a globular particle is preferably less thanabout 1.3, more preferably less than about 1.2, even more preferablyless than about 1.1 and in particular less than about 1.05.

The particles are additionally characterized by their size. The particlesize distribution can be determined by sieve analysis. Unless indicatedotherwise, the particle size refers to the weight average.

The present invention also relates to a product which comprises aplurality of particles. A product of this type comprises a collection ofparticles, typically 50 or more, preferably 100 or more, particles. Aproduct of the invention comprises predominantly particles satisfyingthe particle criteria of the invention. Preferably at least 90%, inparticular at least 95% and very particularly preferably at least 98% ofthe particles have a length-width ratio of less than about 1.4,preferably less than about 1.3, more preferably less than about 1.2,even more preferably less than about 1.1 and in particular less thanabout 1.05.

A process gas jet is utilized according to the invention to guide solidparticles repeatedly past sprayed droplets. The process gas may be forexample air or an inert gas such as nitrogen, carbon dioxide or a noblegas.

Preferred Embodiments

As explained above, it has been found according to the invention that itis possible to produce globular particles from single droplets of amelt. The particles preferably have a compact structure. It is furtherpreferred for the particles to have a homogeneous surface structure. Itis essential in this connection that the build up of globular particlesis made possible by particles which have been introduced or formed fromthe melt repeatedly coming into contact with droplets of the melt, sothat globular particles of a desired size can be built up. For thispurpose, the particles are moved inside a processing chamber with theaid of a process gas jet guided in a defined way. Particles which havereached a desired size can leave the processing chamber.

The process gas jet is essential both for transport of matter and fortransport of heat. The invention achieves, through choice of thetemperature of the process gas jet as a function of the solidificationpoint of the melt, contact being made between the sprayed droplets andparticles which have already solidified to form substantially globularparticles. In particular, the temperature conditions provided in theprocessing chamber are such as to sufficiently delay solidification inorder to make it possible for the particles which are already solid tobe wetted with the sprayed droplets of the melt and for globularstructures to form. On the other hand, the coming into contact with oneanother, and adhesion, of particles with a liquid surface issubstantially prevented according to the invention.

Accordingly, the process gas jet has a temperature which is below thesolidification product of the melt. On the other hand, the temperatureof the process gas jet must not permit immediate solidification ofdroplets sprayed into the processing chamber. The temperature of theprocess gas jet is preferably 10° C. to 40° C. below the solidificationpoint of the melt.

It is preferred according to the invention for droplets of the melt andsolid particles to be brought into contact with one another in a spoutedbed. Spouted bed means that the completely fluidized solid particles arelocated in a closed solid flow which is stable over time. The spoutedbed is generated with the aid of the process gas jet which is guided ina defined way. Three fluidization states or zones are to bedistinguished within the spouted bed. In a first zone or ejection zone,the solid particles are accelerated through the action of the processgas jet which is guided in a defined way, and the particles in this zonemove in the direction of flow of the process gas jet. Typically, theprocess gas jet is guided vertically upwards. Correspondingly, the flowprevailing in the ejection zone of the spouted bed is directedvertically upwards. In a subsequent second zone or fountain zone, theparticles change their direction of flow. The prevailing flow istransverse. Finally, the particles reach a third zone or return zone.The particles therein then show a motion in the opposite direction untilthey finally return to the inflow of the gas flow which is guided in adefined way, and are again entrained by the latter in the first zone.The particles move in the return zone typically under the influence ofgravity.

The melt can be sprayed through two- or multi-fluid nozzles. A furtherpossibility is to use pressurized nozzles for the spraying.Alternatively, droplet formation is possible by rotary atomizers, jetcutters, ultrasonic droplet formers and other devices known to theskilled person.

It is possible according to the invention, by spraying droplets of amelt into the processing chamber and allowing these droplets tosolidify, to form nuclei of solid particles which are then brought intocontact with further droplets in order to form particles of the desiredsize. An alternative or additional possibility in the method is tosupply solid particles from outside. For example, undersized particleswhich have been removed from the process can be returned as nucleusmaterial to the processing chamber. It is likewise possible foroversized particles which have been removed from the process, oragglomerates of particles, to be comminuted by any desired comminutingunit and returned as nucleus material to the processing chamber. It isalso possible to supply particles of different compositions than that ofthe melt. Melt embedding of the supplied particles is possible in thisway.

The particles formed by the method of the invention are removed from theprocessing chamber. The discharge of the finished product material fromthe processing chamber or a transport of material into a furtherdownstream processing chamber can take place in the region of thetransition from the transverse flow to the downwardly directed solidflow. In one embodiment, the particles discharged from the processingchamber are not classified. In another embodiment, the particlesdischarged from the processing chamber are removed in a classifiedmanner through one or more screening apparatuses.

The method of the invention can be carried out for example with the aidof a device as described in DE 103 22 062 A1. The content of theapplication is incorporated in the present application by reference.

The method of the invention is preferably carried out using a device asshown in the appended figure. This is explained in detail below.

The amount of process gas 10 (usually heated air) necessary forsolidifying the particles to be produced is supplied to an inlet airchamber 17 with rectangular cross section 9 and limiting side walls 5.The process gas 10 is distributed in the inlet air chamber 17 and entersthe processing chamber 8 in the form of gas jets 2 through slitapertures 1. The process gas stream which preferably enters the slit 1horizontally is deflected by the deflecting part 3 preferably upwardsinto the processing chamber 8 and flows as a type of free jet into theapparatus. Thereafter it is optionally possible for the cross section ofthe apparatus to become larger in the expansion zone 14 so that thevelocity of the process gas flow steadily diminishes upwards. The gasleaves the apparatus as exit gas 11 above the expansion zone 14 over theexit-air part 19 into which it is optionally possible for a dust-removalsystem (e.g. filter cartridges or textile filter elements) to beintegrated.

Present in the processing chamber 8 is an amount of particles which arecarried upwards by the process gas jet. In the upper region of theprocessing chamber 8, and in the expansion zone 14 located above it, thegas velocity decreases, so that the upward-flowing particles leave thegas jet 23 laterally and fall back into the processing chamber 8. Theprocessing chamber 8 is limited in the lower region by inclined sidewalls 29. Owing to this inclination at the sides, the particles areconveyed under the action of gravity via the return zone 24 in thedirection of the gas-inlet slit 1, where they are subsequently carriedby the process gas back into the processing chamber 8.

This mechanism results in formation of a very uniform solid circulation15 consisting of an upward flow and a return in the direction of theprocess gas inlet. This results in a high particle density in the corezone above the deflecting part 3 even when there are very small amountsof particles in the processing chamber 8. One or more spray nozzles 7are disposed in this region and spray upwards in the same direction asthe process gas jet and serve to introduce the melt.

The high particle loading in the core zone results in very advantageousconditions for heat and material transfer in the nozzle-spraying zone22. A further consequence is that the melt is very substantiallydeposited on the particles and thus wets them uniformly on the particlesurfaces. The uniform wetting with, at the same time, high solidcirculation between nozzle-spraying region and return zone 24 has theeffect that a very uniform liquid film is formed. The melt solidifiesthrough the solidification process, and the solid remains on theparticle surface. This results in very uniform and homogeneous growth ofthe granules, leading to a very narrow particle size distribution and ahomogeneous particle structure.

The process gas may discharge some of the particles, and fines and dust,as solid-loaded exit air 20 from the processing chamber 8. Deposition ofthese particles is possible by using the filter system which isoptionally integrated in the exit-air part 19, or the dust-removalsystems downstream of the apparatus. In the case of an integrateddust-removal system 25, for example, compressed air pulses 18 can beused in order to return the retained particles as removed solid 21 intothe processing chamber 8.

Compared with fluidized bed apparatuses with integrated filter systems,the dust recycling is facilitated by the upwards-directed process gasflow being substantially spatially restricted and thus the particleswhich are to be returned are able reliably to descend outside the gasjet. This mechanism is additionally promoted by the suction effect inthe vicinity of the gas-inlet slit 1. Alternatively, particles depositedfrom the exit air can be returned to the processing chamber 8. For thispurpose, various types of feed 26 can be disposed in the lower region ofthe inclined side walls 29. Owing to the high velocity of the processgas jet in the vicinity of the gas-inlet slit 1, the fine particles aresucked up and supplied to the nozzle-spraying zone 22 where they arewetted with melt and take part in the growth process.

Optionally incorporated guide plates 16 assist the gas jet, enhance thesuction effect and improve the feeding of solids into thenozzle-spraying zone 22. Any agglomeration effects which occur areminimized because very high flow velocities and thus greater separationforces than in fluidized beds occur in the nozzle-spraying region. Thisresults in the particles being separated and growing into granules witha globular shape.

The flow profile of the process gas in the processing chamber 8 has thefurther effect that fine particles returned from the optionallyintegrated filter system into the processing chamber do not fall backinto the nozzle-spraying zone 22. Adhesion of fine particles andconsequent agglomeration processes are suppressed thereby.

To carry out the process continuously, the apparatus can optionally beequipped with various input systems 13 for solids. It is possiblethereby to supply to the process for example particles which can beobtained by comminuting for example (oversized) granules or/and consistof undersized granules. These particles then serve as granulation nucleior as initial charge to shorten the operating time. It is additionallypossible here for additives which are to be incorporated in the granulesto be fed in solid form into the process.

The apparatus can further be provided with discharge elements 4 in orderto be able to remove particles from the processing chamber 8. This cantake place for example by an overflow or by a volumetric dischargeelement (e.g. a star wheel discharger) or else by a gravity separator(e.g. a zig-zag classifier or an ascending pipe classifier supplied withscreening gas).

It is optionally possible to attach mechanical units 27 in theprocessing chamber 8, but preferably in the region of the return zone 24on the inclined walls, in order to generate, by comminution, sufficientfine material as nuclei for the granulation process. The return zone 24can further optionally be used for siting heating devices or otherheat-transfer units 28. For example, the apparatus wall can be jacketedin order to use it for example for heating or cooling the walls byemploying liquid or gaseous heat transfer agents. It is thus possible toadjust optimal surface temperatures in order to avoid for exampledeposits of product.

Spray nozzles 6 which preferably spray downwards, but also partlyupwards, can optionally be disposed in the processing chamber 8 or inthe parts of the apparatus located above, the expansion zone 14 and theexit-air part 19. The liquid formulation can be sprayed in here likewisein order, for example, to produce granulation nuclei by spraydrying/spray congealing in the apparatus. Alternatively, additives orother components in liquid form can be sprayed in through some of thespray units 6 and 7 and thus be incorporated homogeneously into thegranular structure. If the spray nozzles 7 pass through the heated inletair chamber 17, it is optionally possible for the liquid-carrying partsto be provided with insulators or various cooling or heating systems 12in order to diminish damage to the liquid formulation.

A further advantage of the process of the invention which should bementioned is the very simple configuration which combines a high safetyof operation and lack of susceptibility to malfunctioning with very goodcleanability. Improved manufacturing conditions, in particular inrelation to pharmaceutical and hygiene requirements on change ofproduct, are thus created.

Examples

The invention is illustrated by means of specific examples of usewithout being restricted in any way thereby.

Example 1

An ibuprofen melt with a temperature of 110° C. was sprayed into anapparatus which is characterized by the configuration described above.The processing chamber is characterized by a rectangular cross sectionand has a cross-sectional area of 0.15×0.2=0.03 m² and a height of about1 m above the inclined side walls. The process air stream which ispreheated to about 40° C. is supplied at about 150 m³/h through 2 gassupply slits running lengthwise through the apparatus. The melt wassprayed in through a two-fluid nozzle spraying vertically upwards andfed with compressed air into the process air jet with a mass flow rateof about 30 g/min. The spraying air was heated to 90° C. About 500 g ofibuprofen granules were present in the processing chamber. Dust wasremoved from the exit air by a cyclone downstream of the apparatus, andthe deposited solid was fed gravimetrically into the process chamber inthe vicinity of the slit as nucleus material. A zig-zag classifier wasused to remove granules continuously from the front of the processingchamber. The fines separated in the classifier were blown back by thescreening air into the processing chamber. The removed granules have ausual uncompacted apparent density and a usual particle sizedistribution and are thus suitable for further processing. Thus, thefollowing particle size distribution was found (sieve analysis):

-   >400 μm:0.8 mass %-   315 . . . 400 μm:6.8 mass %-   250 . . . 315 μm:15.3 mass %-   160 . . . 250 μm:42.3 mass %-   100 . . . 160 μm:24.9 mass %-   0 . . . 100 μm:9.9 mass %

Example 2

An ibuprofen melt with a temperature of 110° C. was sprayed into anapparatus which is characterized by the configuration described above.The processing chamber is characterized by a rectangular cross sectionand has a cross-sectional area of 0.2×1.0=0.2 m² and a height of about 1m above the inclined side walls. The process air stream which ispreheated to about 45° C. was supplied at about 780 m³/h through 2 gassupply slits running lengthwise through the apparatus. The entireprocess air flow was uniformly distributed to 4 inlet air chambers ofequal size. The previously described processing chamber extents at theupper part along the inlet air chambers and is not subdivided. The meltwas sprayed through two two-fluid nozzles supplied with compressed airand spraying vertically upwards into the process air jet at a total massflow rate of about 22 kg/h. About 6 kg of ibuprofen granules werepresent in the processing chamber. Dust was removed from the exit air bya cartridge filter which was integrated in the apparatus and was cleanedcyclically by pulses of compressed air. The unclassified removal ofgranules from the processing chamber took place at the front using astar wheel discharger. The complete discharged stream of granules wasthen guided into a screening system where an oversized portion (>400 μm)and an undersized portion (<200 μm) were screened off. The undersizedportions removed in the screen were blown back pneumatically into theprocessing chamber. The oversized material was continuously ground in apinned disc mill and likewise conveyed back as granulation nuclei intothe processing chamber. The removed granules (>200 μm and <400 μm) alsohave in this case an adequate uncompacted bulk density which is suitablefor further processing, and adequate particle size distribution which isdetailed below:

-   >400 μm:0.8 mass %-   315 . . . 400 μm:6.8 mass %-   250 . . . 315 μm:15.3 mass %-   160 . . . 250 μm:42.3 mass %-   100 . . . 160 μm:24.9 mass %-   0 . . . 100 μm:9.9 mass %

Reference numbers 1 Slit aperture(s) 2 Gas jet(s) 3 Deflecting part 4Discharge element 5 Side wall 6 Spray nozzle(s) spraying in anydirections 7 Spray nozzle(s) spraying upwards 8 Processing chamber 9Cross section of a process stage 10 Process gas 11 Exit gas 12 Insulatorwith cooling or heating system 13 Input system 14 Expansion zone 15Solid circulation 16 Guide plate(s) 17 Inlet air chamber 18 Pulses ofcompressed air 19 Exit-air part 20 Solid-loaded exit air 21 Removed andreturned solid 22 Nozzle-spraying zone 23 Particle exit from the gas jet24 Return zone 25 Dust removal system 26 Feeds 27 Mechanical comminutingunits 28 Heat-transfer units 29 Side wall

1. Method for producing particles with a length-width ratio of less thanabout 1.4 from a pharmaceutical substance, which method includes thefollowing stages: (a) provision of a melt of the pharmaceuticalsubstance; (b) production of droplets of the melt by spraying into aprocessing chamber; (c) repeated guiding of solid particles past sprayeddroplets in the processing chamber with the aid of a process gas jetwhich is guided in a defined way and whose temperature is fixed,depending on the solidification point of the melt, so that at least someof the droplets come into contact with particles and solidify thereon;(d) removal of particles from the processing chamber as a function ofthe particle size.
 2. Method according to claim 1, where the averageparticle size of the produced particles is in the range from 0.1 to 3mm.
 3. Method according to claim 1 or 2, where the length-width ratio ofa particle is less than about 1.3, preferably than about 1.2, morepreferably less than about 1.1 and in particular less than about 1.05.4. Method according to any of claims 1 to 3, where a spouted bed offluidized solid particles is formed in the processing chamber.
 5. Methodaccording to any of claims 1 to 4, where solid particles are guided pastsprayed droplets by spraying droplets of the melt into the spouted bed.6. Method according to claim 5, where the droplets of the melt aresprayed into the spouted bed in the region of the ejection zone. 7.Method according to claim 6, where the droplets are sprayed in the samedirection as the process gas jet.
 8. Method according to claim 6 or 7,where the droplets are sprayed into the ejection zone in the regionadjoining the return zone.
 9. Method according to any of claims 1 to 8,where the temperature of the process gas jet which is guided in adefined way is 10° C. to 40° C. below the solidification point of themelt.
 10. Method according to any of claims 1 to 9, where the meltrepresents a homogeneous liquid phase.
 11. Method according to any ofclaims 1 to 9, where the melt comprises solid substances dispersedtherein.
 12. Method according to any of claims 1 to 11, where solidparticles are introduced into the processing chamber from outside. 13.Method according to any of claims 1 to 12, where the pharmaceuticalsubstance is an active pharmaceutical ingredient.
 14. Method accordingto claim 13, where the active pharmaceutical ingredient is ibuprofen.15. Particles of a pharmaceutical substance, where the particles have anaverage particle size of from 0.1 to 3 mm and a length-width ratio ofless than about 1.4 and are produced from a melt of the pharmaceuticalsubstance.
 16. Particles according to claim 15, produced by a methodaccording to any of claims 1 to
 14. 17. Collection of particles asdefined in claim 15 or
 16. 18. Use of particles as defined in claim 15or 16 or of a collection according to claim 17 for producing apharmaceutical dosage form.